Transmembrane ion flux via channels, transporters, and pumps plays a critical role in diverse physiologic functions, including neuronal signal transmission and electrolyte and volume homeostasis. In many cases, homologous electrolyte flux processes in different tissues are mediated by the encoded products of distinct genes, while in a few cases the identical gene products are involved. Evidence of the latter comes from Mendelian diseases in which mutation in a single gene produces effects on both auditory and renal function. For example, loss-of-function mutations in ATP6B1, which encodes a subunit of the H+-ATPase, result in systemic acidosis because of a renal defect in H+ secretion and sensorineural hearing loss caused by defective H+ secretion into the cochlear endolymph, resulting in impaired hair cell function and deafness (Karet et al., 1999, Nature Genetics 21:84-90). Similarly, mutations in barttin, an accessory subunit of the CLCNKA and CLCNKB chloride channels, result in renal salt wasting and deafness (Birkenhager et al., 2001, Nature Genetics 29:310-314).
The genetic dissection of renal diseases featuring low serum potassium (hypokalemia) and metabolic alkalosis (high serum pH) has identified many components required for normal renal electrolyte homeostasis (Birkenhager et al., 2001, Nature Genetics 29:310-314; Hansson et al., 1995, Nature Genetics 11:76-82; Simon et al., 1997, Nature genetics 17:171-178; Simon et al., 1996, Nature genetics 13:183-188; Simon et al., 1996, Nature Genetics 14:152-156; Simon et al., 1996, Nature Genetics 12:24-30). In all cases, this syndrome has resulted from increased activity of the epithelial Na+ channel (ENaC) on the apical membrane, which leads to increased secretion of K+ and H+ because of the more negative luminal potential. Hypokalemia with alkalosis can result either from primary increases in ENaC activity because of mutations in ENaC itself (Hansson et al., 1995, Nature Genetics 11:76-82), or from activation of ENaC by aldosterone in response to reduced intravascular volume (Simon et al., 1996, Nature Genetics 12:24-30). Mutations that cause impaired salt reabsorption in the thick ascending limb of Henle or the distal convoluted tubule cause salt wasting that leads to secondary increases in ENaC activity and hypokalemic alkalosis. These diseases, referred to as Bartter and Gitelman syndromes, are associated with mutations in genes encoding apical Na+—Cl− transporters that mediate Na+—Cl− entry into epithelia, Cl− channel subunits that mediate exit of across the basolateral membrane, and an apical K+ channel (Birkenhager et al., 2001, Nature Genetics 29:310-314; Simon et al., 1997, Nature genetics 17:171-178; Simon et al., 1996, Nature genetics 13:183-188; Simon et al., 1996, Nature Genetics 14:152-156; Simon et al., 1996, Nature Genetics 12:24-30). These syndromes are distinguished clinically by marked hypomagnesemia and low urinary calcium in Gitelman syndrome, while hypercalciuria with normal or modest reductions in Mg2+ is observed in Bartter syndrome.
Similarly, a number of Mendelian seizure disorders have been described. Many of these result from mutations that depolarize neurons, increasing neuronal excitability and reducing seizure threshold. Examples include benign familial neonatal seizures caused by mutations in the KCNQ2/3 K+ channels (Biervert et al., 1998, Science 279:403-406; Charlier et al., 1998, Nature Genetics 18:53-55), benign familial neonatal/infantile seizures caused by mutations in the SCN2A gene encoding the alpha subunit of voltage gated Na+ channels (Heron et al., 2002, Lancet 360:851-852), and several idiopathic epilepsy syndromes caused by mutations in the SCN1A sodium channel (Weber et al., 2008, Dev. Med. Child. Neurol. 50:648-654).
Considering the many similarities in the mechanisms governing renal electrolyte homeostasis and neuronal function, it is surprising that relatively few single-gene disorders that have effects on both have been identified. Here, we describe a previously unrecognized complex syndrome featuring seizures, sensorineural deafness, ataxia, mental retardation and electrolyte imbalance (SeSAME), and demonstrate that it is caused by mutation in KCNJ10, which encodes a K+ channel expressed in epithelia of the kidney and inner ear, as well as glial cells in the CNS.
There is need in the art for compositions and methods to diagnose and treat subjects afflicted with SeSAME syndrome. The present invention fulfills this need.